Folate receptor-mediated enhanced and specific delivery of far-red light-activatable prodrugs of combretastatin A-4 to FR-positive tumor

Gregory Nkepang, Moses Bio, Pallavi Rajaputra, Samuel G. Awuah, Youngjae You

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

We examined the concept of a novel prodrug strategy in which anticancer drug can be locally released by visible/near IR light, taking advantage of the photodynamic process and photo-unclick chemistry. Our most recently formulated prodrug of combretastatin A-4, Pc-(L-CA4)2, showed multifunctionality for fluorescence imaging, lightactivated drug release, and the combined effects of PDT and local chemotherapy. In this formulation, L is a singlet oxygen cleavable linker. Here, we advanced this multifunctional prodrug by adding a tumor-targeting group, folic acid (FA). We designed and prepared four FA-conjugated prodrugs 1-4 (CA4-L-Pc-PEGn-FA: n = 0, 2, 18, -45) and one non-FAconjugated prodrug 5 (CA4-L-Pc-PEG18-boc). Prodrugs 3 and 4 had a longer PEG spacer and showed higher hydrophilicity, enhanced uptake to colon 26 cells via FR-mediated mechanisms, and more speci fic localization to SC colon 26 tumors in Balb/c mice than prodrugs 1 and 2. Prodrug 4 also showed higher and more specific uptake to tumors, resulting in selective tumor damage and more effective antitumor efficacy than non-FA-conjugated prodrug 5. FR-mediated targeting seemed to be an effective strategy to spare normal tissues surrounding tumors in the illuminated area during treatment with this prodrug. (Chemical Equation Presented).

Original languageEnglish
Pages (from-to)2175-2188
Number of pages14
JournalBioconjugate Chemistry
Volume25
Issue number12
DOIs
StatePublished - Dec 17 2014

Bibliographical note

Publisher Copyright:
© 2014 American Chemical Society.

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

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